1. Field of the Invention
The present invention relates to Osteomeles schwerinae extract and the systematic fractions thereof which can be used as a pharmaceutical composition for the prevention and treatment of diabetic complications, and can be applied to a functional food as well.
2. Description of the Related Art
Diabetes is one of the critical adult diseases drawing our attention world-widely. Recently prevalence rate of diabetes reaches 10% in Korea, which has been growing along with the rapid growth of economy. The number of diabetes patients counts more than 240,000,000 over the world and is expected to reach 380,000,000 in 2025. It was presumed by JAMA, USA, in 2009 that 60% of the expected total diabetes would be reported in Asia. The time of onset of diabetes is tended to be earlier now, which seems to be largely the group of middle age. As life-time is extended, it is very hard to avoid complications. For instance, after 10-20 years from the onset of diabetes, almost every body organ is damaged to cause diabetic retinopathy, diabetic cataract, diabetic nephropathy, diabetic neuropathy, heart disease, cancer, and osteoporosis, etc. Chronic diabetic nephropathy requires hemodialysis and can be a critical reason of end stage renal disease. Diabetic cataract and diabetic retinopathy cause sight loss and even lead to death. In USA, the major reason of sight loss in the age group of 25-74 is diabetes. For example, 60% of diabetics lose their eye sight 15-20 years after the onset. Therefore, only if the occurrence of complications is postponed 5-10 years, the quality of life of a diabetic and his family will be totally different, affecting the national budget itself.
The mechanisms that cause diabetic complications are explained by nonenzymatic glycation of protein, polyol pathway, and oxidative stress, etc.
Nonenzymatic glycation of protein indicates condensation reaction of reducing sugar and amino acid group such as lysine residue of protein, which is Maillad reaction, without being mediated by enzyme. As a result of this reaction, advanced glycation endproducts (AGEs) are generated. Nonenzymatic glycation of protein is explained in more details: (1) amino acid group such as lysine residue of protein is reacted with aldehyde or ketone of reducing sugar without enzyme activity, which is nucleophilic addition, to produce the early stage product schiff base, and then ketoamine adducts residing close to the schiff base are reacted each other by condensation to produce reversible Amadori type early glycation products; and (2) when hyperglycemia status is longer, the reversible Amadori type early glycation products are not degradated and only rearranged to produce irreversible advanced glycation endproducts. The generated irreversible advanced glycation endproducts are conjugated or cross-linked with protein or lipid, leading to the generation of irreversible glycoprotein or glycolipid.
Unlike the reversible Amadori type early glycation product, the irreversible advanced glycation endproduct is not degradated once it is generated, even when the blood glucose level is recovered to normal, and is accumulated in tissues as long as the protein or lipid to which the advanced glycation endproduct is conjugated exists, resulting in abnormal changes in structure and function of tissues to cause complications (Vinson, J. A. et al., 1996, J. Nutritional Biochemistry 7: 559-663; Smith, P. R. et al., 1992, Eur. J. Biochem., 210: 729-739).
For example, glycated albumin, one of the advanced glycation endproducts generated by the reaction between glucose and many kinds of proteins, is a critical cause of chronic diabetic nephropathy. Glycated albumin can be introduced into glomerular cells more easily than normal albumin. High concentration of glucose stimulates mesangium cells to increase extracellular matrix synthesis. Because of excessive glycated albumin introduced therein and increased extracellular matrix, glomerular fibrosis is induced. By such mechanism, glomerulus is continuously damaged, and at last extreme care such as hemodialysis or organ transplantation is required. As chronic diabetes continues, collagen is conjugated with the advanced glycation endproduct in arterial wall and also basement membrane protein is conjugated with the advanced glycation endproduct in glomerulus, which are accumulated in tissues (Brownlee, M., et al., 1986, Sciences, 232, 1629-1632).
Such nonenzymatic glycation of protein induces glycosylation of basement membrane, plasma albumin, lens protein, fibrin, and collagen, and the advanced glycation endproduct generated thereby causes abnormal changes in the structure and functions of tissues, leading to chronic diabetic complications such as diabetic retinopathy, diabetic cataract, diabetic nephropathy, and diabetic neuropathy.
Under the condition of hyperglycemia, when the advanced glycation endproduct is produced, lipid metabolism disorder is induced and at the same time defense system against toxic oxygen free radical is weakened to cause oxidative stress (Yokozawa, T., et al, 2001, J. of Trad. Med., 18: 107-112). So, nonenzymatic glycation of protein is closely related to oxidative stress mechanism.
Polyol pathway is the process composed of the following steps: (1) Aldose or ketose is reduced by aldose reductase (AR) to generate sorbitol; and (2) The sorbitol is oxidized by dehydrogenase to produce fructose. In normal condition, aldose reductase exhibits very low affinity to glucose. However, under hyperglycemia condition, aldose reductase, the first enzyme of polyol pathway, is over-activated, and thus excessive blood glucose is converted to sorbitol and fructose, which are accumulated in tissues with breaking the balance of osmotic pressure, resulting in complications. That is, increased osmotic pressure drags moisture, leading to diabetic retinopathy, diabetic cataract, and diabetic neuropathy (Diabetes, Kim, et al., Korean Diabetes Association, Korea Medical Book Publisher, 483; Soulis-Liparota, T., et al., 1995, Diabetologia, 38: 357-394).
It was reported that the advanced glycation endproduct activates aldose reductase (AR), the main enzyme of polyol pathway, in human microvascular endothelial cells (Nakamura, N., et al., 2000, Free Radic Biol. Med., 29: 17-25). At this time, the speed of nonenzymatic glycation of fructose is approximately 10 times as fast as glucose. So, when high concentration of fructose is conjugated with protein, the generation of the advanced glycation endproduct is accelerated.
The mechanisms of nonenzymatic glycation of protein, polyol pathway, and oxidative stress are all connected to cause diabetic complications. So, it is very important to inhibit the generation of advanced glycation endproduct to postpone, prevent or treat diabetic complications (Brownlee, M., et al., 1988, N. Engl. Med., 318, 1315-1321).
Aminoguanidine, the synthetic protein glycosylation inhibitor, is nucleophilic hydrazine, which is conjugated with Amadori product to intervene cross-linking of protein, resulting in the inhibition of the generation of advanced glycation endproduct, by which it can postpone or prevent the progress of diabetic complications (Brownlee, M., et al., 1986, Sciences, 232, 1629-1632; Edelstein, D. et al., 1992, Diabetes, 41, 26-29). Therefore, aminoguanidine has been known as the promising synthetic medicine for the prevention and treatment of diabetic complications, and thus the third phase clinical test has been completed. However, the clinical test of aminoguanidine has been stopped because of its toxicity observed during the long term administration. Accordingly it is an urgent request to develop a safer and more effective natural drug.
Thus, the present inventors have tried to develop a composition for the treatment of diabetic complications using natural substances and at last the inventors completed this invention by confirming that Osteomeles schwerinae extract and its fractions have anti-diabetes, anti-aging and anti-cancer effects.